Case Report

Lymphoma With Features Intermediate Between Aggressive T-Large Granular Lymphocytic Leukemia and Hepatosplenic T-Cell Lymphoma: A Diagnostic Dilemma? Chi Young Ok,1 C. Cameron Yin,1 Mariko Yabe,2 Carlos E. Bueso-Ramos,1 Roberto N. Miranda,1 L. Jeffrey Medeiros,1 Sergej N. Konoplev1 Clinical Practice Points  T-large granular lymphocytic leukemia (T-LGLL) is an

indolent neoplasm that usually arises in older adults and is characterized by persistent (> 6 months) large granular lymphocytosis (> 2000/mL). The leukemic cells usually express T-cell receptor (TCR) ab, CD3, CD8, and CD57. Rare cases of T-LGLL with an aggressive clinical course have been reported.  Hepatosplenic T-cell lymphoma (HSTCL) is an aggressive neoplasm that usually arises in young adults.

The lymphoma cells usually express TCR gd, CD3, and CD56, and are CD4 negative (CD4), CD8/þ, and CD57. A small subset of HSTCL cases can express TCR ab.  Distinguishing between an aggressive variant of T-LGLL and HSTCL can be difficult. We present 2 patients with T-cell neoplasms with features of T-LGLL and HSTCL that illustrate the issue.

Clinical Lymphoma, Myeloma & Leukemia, Vol. 14, No. 3, e95-100 ª 2014 Elsevier Inc. All rights reserved. Keywords: Hepatosplenic T-cell lymphoma, T-LGL leukemia

Introduction T-large granular lymphocytic leukemia (T-LGLL) is usually a clinically indolent disease characterized by a monoclonal proliferation of large granular lymphocytes involving peripheral blood, bone marrow, spleen, and liver.1 When treatment is necessary, patients with T-LGLL are commonly managed using single-agent immunosuppressive therapy, most often methotrexate or cyclophosphamide.2 Hepatosplenic T-cell lymphoma (HSTCL), in contrast, is an aggressive disease characterized by proliferation of T-cells in the spleen, liver, bone marrow, and peripheral blood.3,4 Because of the rarity of this disease, treatment guidelines for patients with HSTCL have yet to be established; chemotherapy followed by 1 Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 2 Department of Pathology, St Luke’s-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, NY

Submitted: Dec 6, 2013; Revised: Dec 27, 2013; Accepted: Dec 27, 2013; Epub: Jan 2, 2014 Address for correspondence: Sergej Konoplev, MD, PhD, Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009 Fax: 713-792-4821; e-mail contact: [email protected]

2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2013.12.017

stem cell transplantation is usually recommended.5 In most patients, distinguishing T-LGLL and HSTCL can be accomplished on the basis of clinical, morphologic, immunophenotypic, cytogenetic, and molecular information. In a small subset of patients, however, T-cell neoplasms can exhibit overlapping features of T-LGLL and HSTCL, and these cases can be challenging. In this report, we present 2 patients to illustrate T-cell neoplasms with overlapping features of T-LGLL and HSTCL.

Case Reports Case 1

A 46-year-old man presented in November, 2010 with pancytopenia. His medical history was significant for right orchiectomy and radiation therapy for seminoma (T1N1M0) in March, 2008. A complete blood count (CBC) showed: white blood count (WBC) 1
109/L (normal range, 4-11
109/L), neutrophil absolute count 0.4
109/L (normal range, 1.7-7.3
109/L), hemoglobin 111 g/L (normal range, 140-180 g/L), and platelet count 96
109/L (normal range, 150-440
109/L). A decreased haptoglobin level of < 8 mg/dL (normal range, 30-200 mg/dL), increased reticulocyte count of 2.7% (normal range, 0.5%-1.5%), and increased indirect bilirubin level of 1.1 mg/dL (normal range, 0.1-0.4 mg/dL) raised

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Diagnostic Dilemma: T-LGLL Versus. HSTCL

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the possibility of hemolysis, but direct Coombs test was negative for immunoglobulin (Ig)G and C3. A computed tomography (CT) scan showed splenomegaly (18 cm) without evidence of abdominal and pelvic lymphadenopathy. Bone marrow aspiration and biopsy did not detect any evidence of a myelodysplastic syndrome or lymphoproliferative disorder. Flow cytometric immunophenotypic analysis of bone marrow aspirate using a large panel of markers did not show any abnormalities. Conventional cytogenetic analysis showed: 46,XY,inv(9),inv(Y) in all 20 metaphases. The inv(9) and inv(Y) were observed in all metaphases of all subsequent cytogenetic studies and most likely represent constitutional changes of no known clinical significance. Fluorescence in situ hybridization (FISH) analysis did not show any chromosomal abnormalities using probes specific for ATM (ataxia telangiectasia mutated), D12Z3, D13S319, LAMP1 (lysosomal-associated membrane protein 1), TP53 (tumor protein p53), and 30 IgH/50 IgH. The patient’s blood counts improved with prednisone therapy, 60 mg per day, however, pancytopenia persisted. A second bone marrow aspiration and biopsy performed 6 months later showed orderly trilineage hematopoiesis with the same cytogenetic abnormalities identified previously. Therapy was switched to rituximab with methylprednisolone sodium succinate (Solu-medrol), but persistent pancytopenia eventually led to splenectomy being performed 4 months later for therapeutic and diagnostic purposes. The spleen weighed 1095 g and was 24 cm in the greatest dimension. No gross lesions were found. Microscopically, the splenic red pulp was diffusely infiltrated by small lymphoid cells with dense nuclear chromatin, irregularly-shaped nuclei, and scant cytoplasm. Large atypical cells or necrosis were not present. Small areas of residual white pulp were identified (Fig. 1A). Immunohistochemical studies showed that the small neoplastic cells were of T-cell lineage with a cytotoxic immunophenotype: CD3positive (CD3þ), CD4, CD5, CD7þ, CD8, CD20, CD56 (subset)þ, CD57, CD68 (PG-M1), CD79a, granzyme Bþ, PAX-5 (paired box), and TIA-1þ (TIA1 cytotoxic granuleassociated RNA binding protein) (Fig. 1B-D). In situ hybridization study for Epstein-Barr virus-encoded RNA (EBER) was negative. Flow cytometric immunophenotypic analysis was not performed. Polymerase chain reaction (PCR) performed on splenic tissue showed monoclonal rearrangement of the T-cell receptor (TCR) b and g chain genes. HyperCVAD (hyperfractionated cyclophosphsmide, vincristine, doxorubicin and dexamethasone) chemotherapy was started for the patient. Follow-up bone marrow examination in June, 2012 showed a hypercellular (70%-80%) bone marrow with extensive involvement by a T-cell lymphoproliferative disorder. The lymphoid cells were pleomorphic and some of these cells had small cytoplasmic granules (Fig. 1E-H). Flow cytometric immunophenotypic analysis demonstrated an aberrant T-cell population: CD2þ, CD3 dimþ, CD4, CD5þ, CD7, CD8 very dimþ, CD25 brightþ, CD26, CD52 very dimþ, CD56 brightþ, TCR a/b dimþ, and TCR g/d. PCR performed on bone marrow aspirate material showed monoclonal rearrangements of the TCR b and g chain genes. Of interest, the size of the monoclonal PCR products of the TCR b chain gene (265 base pairs) and TCR g chain gene (250 base pairs) detected in the bone marrow were similar to the PCR products detected previously in the spleen sample. Furthermore, the TCR g assay also

Clinical Lymphoma, Myeloma & Leukemia June 2014

showed that the rearrangements in the bone marrow and spleen specimens used the same V gamma I family.6 These results indirectly support a clonal relationship between the neoplastic processes in the spleen and bone marrow. Conventional cytogenetic analysis showed the known abnormalities. FISH studies using a D7S522/CEP7 dual color probe did not detect any abnormalities of chromosome 7. The poor response of the neoplasm to any type of therapy raised a concern of hepatosplenic T-cell lymphoma. The patient underwent stem cell transplant from an human leukocyte antigen-matched unrelated donor in August, 2012. In January 2013 the patient relapsed with leptomeningeal involvement and was treated with cytarabine, methotrexate, and hydrocortisone, followed by radiotherapy. In May 2013 the patient developed peripheral blood involvement with 78% lymphoma cells; bone marrow aspiration and biopsy showed a T-cell neoplasm involving nearly 100% of the bone marrow cellularity with immunophenotype similar to a previous bone marrow study. The patient developed paraplegia, stress cardiomyopathy, and bacteremia, and subsequently expired in elected home hospice care.

Case 2 A 44-year-old woman with an otherwise unremarkable medical history underwent a clinical work-up for menorrhagia and was discovered to have lymphocytosis in April, 2012. Physical examination revealed hepatosplenomegaly; the spleen was approximately 3 cm below the costal margin (liver was not quantified). A CBC showed: WBC 20
109/L with absolute lymphocyte count of 18.3
109/L (normal range, 1
109/L), hemoglobin 128 g/L, hematocrit 41% (normal range, 40%-54%), and platelet 142
109/L. Flow cytometry immunophenotypic analysis of peripheral blood showed that 82% of total analyzed cells were T-cells with expression of CD2, CD3, CD5, CD7, CD8, CD26, CD27 (partial), CD57, and human leukocyte antigen-D related (HLA-DR). No immunophenotypic aberrancies were observed. Serum testing showed an antinuclear antibody at 1:640. The diagnosis of T-LGLL was established, and the physician recommended observation because the patient did not meet the treatment criteria for the large granular lymphocytic leukemia, such as recurrent infections, neutropenia, and symptomatic anemia. Six months later, she developed a generalized feeling of malaise, increasing fatigue and lethargy, low-grade fevers with intermittent spikes up to 101 F, and a waxing and waning generalized skin rash with pruritus. Methotrexate treatment was started (7.5 mg weekly), but the patient had mouth sores, lethargy, night sweats, and intermittent fever up to 101 F. A CT scan performed in November, 2012 showed hepatomegaly (25 cm), splenomegaly (18 cm), abdominal lymphadenopathy including a lymph node in the porta hepatis, and cholelithiasis. Because of no measurable benefit from methotrexate, the patient was switched to cyclosporine therapy. On a follow-up visit in February, 2013, abnormal laboratory findings included: b2 microglobulin 7.8 mg/L (normal range, 1.22.8 mg/L), lactate dehydrogenase 227 U/L (normal range, 100-190 U/L), and alkaline phosphatase 291 U/L (normal range, 25-110 U/L). A CBC showed: WBC 17.4
109/L, hemoglobin 111 g/L, hematocrit 34.2%, and platelet count of 66
109/L. A differential cell count showed 90% lymphocytes, 8% segmented neutrophils, 1% bands, and 1% eosinophils and morphologic review of the peripheral blood smear showed lymphocytosis. The lymphocytes were

Chi Young Ok et al Figure 1 Various Images of Case 1. (A) Spleen Red Pulp is Infiltrated by Small Neoplastic Cells (H & E; Magnification 3400). (B-D) The Neoplastic Cells Involving Spleen Express CD3 (B) and Granzyme B (D) and are Negative for CD8 (C) (Immunochemistry; Magnification 3400). (E) Bone Marrow Biopsy Shows Interstitial Infiltrate (H & E; Magnification 3500). (F-H) The Neoplastic Cells Involving Bone Marrow Express CD3 (F), Granzyme B (G), and TIA-1 (H) (Immunochemistry; Magnification 3500)

H & E ¼ hematoxylin and eosin; TIA ¼ TIA1 cytotoxic granule-associated RNA-binding protein.

of medium size with dense nuclear chromatin, and abundant pale cytoplasm with azurophilic cytoplasmic granules (Fig. 2A). Flow cytometry immunophenotypic analysis of peripheral blood showed that 88% of the analyzed cells were T-cells positive for CD2, CD3, CD5, and CD8. There was also reduced expression of CD7. The neoplastic cells were negative for CD4, CD16, and CD56. Bone marrow aspiration and biopsy showed hypercellular (90%-100%) bone marrow diffusely effaced by predominantly small lymphoid cells with dense nuclear chromatin and scant cytoplasm (Fig. 2B).

The bone marrow aspirate smears demonstrated increased lymphocytes, predominantly of medium size, with dense nuclear chromatin and abundant cytoplasm. Occasional lymphocytes contained coarse cytoplasmic granules. Immunohistochemical studies performed using fixed, paraffin-embedded sections showed that T-cells were positive for granzyme B and TCR ab, and were negative for CD57 and TCR g (Fig. 2C and D). Conventional cytogenetic studies showed a normal karyotype. FISH analysis using a probe (D7S486/ CEP7) for 7q31 showed no evidence of isochromosome 7q.

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Diagnostic Dilemma: T-LGLL Versus. HSTCL Figure 2 Various Images of Case 2. (A) Peripheral Blood Smear Demonstrates Numerous Large Granular Lymphocytes (Wright Giemsa; Magnification 31000). (B) Bone Marrow Biopsy Specimen Shows Diffuse Lymphocytic Infiltrate (H & E; Magnification 3400). (C) and (D) The Neoplastic Cells Involving Bone Marrow Express CD3 (C; Magnification 3400) and Granzyme B (D; Magnification 31000). (E) and (F) The Neoplasm Infiltrates Liver in a Sinusoidal (E) and Diffuse Pattern (F) (H & E; Magnification 3400). (G) and (H) The Neoplastic Cells Involving Liver Express CD3 (G), Granzyme B (G, Inset), and CD8 (H) (Immunochemistry; Magnification 3400)

H & E ¼ hematoxylin and eosin.

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Liver biopsy, performed a few days after bone marrow examination, showed liver parenchyma extensively infiltrated by neoplastic cells. The neoplastic cells were small- to medium-sized with dense nuclear chromatin and scant cytoplasm. These cells filled and expanded the portal tracts and infiltrated sinusoids (Fig. 2E and F). Degenerative changes in hepatocytes near the portal tracts and cholestasis were also present. Immunohistochemical studies performed using fixed, paraffin-embedded tissue

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sections showed that the neoplastic cells were positive for CD2, CD3, CD5, CD8, and granzyme B, and negative for CD4 and CD57 (Fig. 2G and H). An in situ hybridization study for EBER was negative.

Discussion T-large granular lymphocytic leukemia is typically a clinically indolent disease characterized by a monoclonal proliferation of large

Chi Young Ok et al granular lymphocytes involving peripheral blood, bone marrow, spleen, and liver with expression of TCR ab, CD3, CD8, CD16, and CD57.1 Rarely, T-LGLL can be clinically aggressive.7-13 Compared with patients with classical T-LGLL, patients with aggressive T-LGLL are generally younger and commonly have symptoms of acute illness characterized by hepatosplenomegaly, lymphadenopathy, variable degrees of anemia and/or thrombocytopenia, and usually short survival (approximately several months to 2 years).7 Expression of CD56 has been reported to be a poor prognostic marker, but this observation is not broadly accepted by others.14 Hepatosplenic T-cell lymphoma was initially described as an aggressive disease, involving spleen, liver, and bone marrow without lymphadenopathy.3,4 Neoplastic cells are usually positive for CD3, CD8, CD56, and TCRgd, but a small subset of cases can express TCRab.15 Isochromosome 7q has been reported in a subset of HSTCL cases.16 HSTCL of ab type (HSTCL ab) shares similar clinical, morphologic, and cytogenetic findings to HSTCL of gd type (HSTCL gd).17-19 Some differences have been reported. In contrast with HSTCL gd, which tends to affect younger men (median age, 25 years), HSTCL ab more often affects women, and patients tend to be slightly older (median age, 36 years) at presentation.18 Compared with the usual immunophenotype of CD8þ/CD56þ/CD57/granzyme B in HSTCL gd, CD8/CD56/CD57/and granzyme B are more commonly expressed in HSTCL ab. Table 1 Comparison Between Aggressive T-LGLL and HSTCL ab Type Variable

Aggressive T-LGLL

Median Age, Years

HSTCL ab Type

41

35

Sex

No predilection

Female predilection

B Symptoms

Common

Common

Hepatosplenomegaly Common

Common

Lymphadenopathy

Common

Not common

Anemia

Variable

Variable

Neutropenia

Variable

Variable

Thrombocytopenia

Variable

Variable

Autoimmunity

Associated

Not associated

Clinical Course

Aggressive

Aggressive

Tumor Cells PB

Increased LGLs

LGLs can be seen

BM

Interstitial/intrasinusoidal

Interstitial/intrasinusoidal

Spleen

Cords and sinuses

Cords and sinuses

Liver

Sinusoidal

Sinusoidal

Immunophenotype

CD3þ, CD4, CD8þ, CD56þ/, CD57þ/

CD3þ, CD4, CD8þ/, CD56þ/, CD57þ

Cytotoxic Granules

TIA-1þ, granzyme Bþ, perforinþ

TIA-1þ, granzymeþ/, perforin NA

Isochromosome 7q

Absent

Present

TCR Gene Rearrangement

Clonally rearranged

Clonally rearranged

BM ¼ bone marrow; HSTCL ¼ Hepatosplenic T-cell lymphoma; LGL ¼ large granular lymphocyte; NA ¼ not applicable; PB ¼ peripheral blood; TCR ¼ T-cell receptor; TIA ¼ TIA1 cytotoxic granule-associated RNA-binding protein; T-LGLL ¼ T-large granular lymphocytic leukemia.

In most patients, classical T-LGLL can be distinguished from HSTCL gd on the basis of the clinical, immunophenotypic, and cytogenetic findings. However, as the 2 cases reported here illustrate, the aggressive variant of T-LGLL and HSTCL ab share many features and can be difficult to distinguish (Table 1).7-13,17-19 Lymphadenopathy is uncommon (approximately 15%) in HSTCL ab, but is common in aggressive T-LGLL.18 An association with autoimmunity is almost exclusively observed in patients with aggressive T-LGLL. Morphologically, the presence of large granular lymphocytes is not a unique feature for aggressive T-LGLL because azurophilic cytoplasmic granules can be identified in the atypical lymphoid cells of HSTCL ab.18 Immunophenotypically, CD8 and CD57 are commonly expressed in classical T-LGLL, and CD8 and CD56 are expressed in HSTCL gd. However, CD56 expression is not uncommon in aggressive T-LGLL, and CD8 and CD57 expression is present in half of the cases of HSTCL ab. An activated cytotoxic immunophenotype (granzyme Bþ) is usually not expressed in HSTCL gd, but it is present in almost half of the cases of HSTCL ab.18 The presence of isochromosome 7q is a very helpful feature that supports HSTCL, but its absence does not exclude the diagnosis of HSTCL. Therefore, at times the designation as aggressive T-LGLL versus. HSTCL ab can seem arbitrary. Because of the rarity of aggressive variants of T-LGLL, in our experience, HSTCL ab is thought most likely on this basis alone. The diagnostic dilemma we illustrate is partly explained by the lack of a clear understanding of the molecular pathogenesis of these entities. Recently, others have used molecular methods to characterize underlying genetic and/or genomic aberrations in T-LGLL and HSTCL. Daibata et al conducted gene expression profiling (GEP) on 1 indolent and 1 aggressive T-LGLL cell line. Their results showed many genes overexpressed in the aggressive T-LGLL cell line including dek, AKT1 (v-akt murine thymoma viral oncogene homolog 1), STMN1 (stathmin 1), Id2 (inhibitor of DNA binding 2, dominant negative helix-loop-helix protein), and ATF4 (activating transcription factor 4).13 Travert et al performed GEP on HSTCL of gd and ab type and showed that S1PR5 (sphingosine-1-phosphate receptor 5) and ABCB1 (ATP-binding cassette, sub-family B (MDR/ TAP), member 1) were overexpressed and AIM1 (absent in melanoma 1) was underexpressed in HSTCL compared with peripheral T-cell lymphoma, not otherwise specified.20 However, GEP data directly comparing aggressive T-LGLL with HSTCL ab are not available at the moment. Recently, signal transducer and activator of transcription 3 (STAT3) mutations were reported in up to a third of patients with T-LGLL. Almost all of the mutations were located in the Src homology 2 domain. Y604F and D661Y were the 2 most common mutations and these mutations showed enhanced transcriptional activity in functional studies.21 Although STAT3 mutations do not seem to predict adverse outcome in patients with T-LGLL, this mutation can be diagnostically useful because STAT3 mutations have not been reported in HSTCL.22

Conclusion Aggressive T-LGLL and HSTCL ab can exhibit many overlapping features, and this differential diagnosis might be another gray zone in the classification of lymphoid neoplasms. The detection of isochromosome 7q, although not invariable, supports HSTCL

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Diagnostic Dilemma: T-LGLL Versus. HSTCL ab whereas lymphadenopathy, STAT3 mutations, and an association with autoimmune disease supports T-LGLL. Recently, studies using GEP have provided data that might be helpful in distinguishing T-LGLL from HSTCL ab in the future.

Disclosure The authors have stated that they have no conflicts of interest.

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